Reviews & Analysis

Spindle orientation plays a pivotal role in tissue morphogenesis. An asymmetric anthrax receptor cap is revealed to promote activation of a formin to orient the spindle along the planar cell polarity (PCP) axis in zebrafish dorsal epiblast cells.

Genome sequencing and RNAi have been powerful allies in the quest to assign function to every gene. Systematic RNAi screens identify essential genes efficiently, but are less effective with pleiotropic or redundant genes. A common trick used by geneticists to overcome this problem is to screen for genetic interactors — mutations that enhance or suppress the phenotype of a starting mutation. Now, this classic approach has been combined with the versatility of RNAi to generate an expanded gene network for cell polarity.

Primordial germ cell (PGC) development in the human fetus remains relatively uncharted. A new study suggests that epigenetic reprogramming and sex differentiation in human PGCs occur asynchronously over an extended time period. This finding raises questions and implications for in vitro PGC differentiation.

Epithelial cells have an apical–basolateral axis of polarity, which is required for epithelial functions including barrier formation, vectorial ion transport and sensory perception. Here we review what is known about the sorting signals, machineries and pathways that maintain this asymmetry, and how polarity proteins interface with membrane-trafficking pathways to generate membrane domains de novo.It is becoming apparent that membrane traffic does not simply reinforce polarity, but is critical for the generation of cortical epithelial cell asymmetry.

Basal cell carcinoma has been shown to originate from activation of hedgehog signalling in interfollicular epidermal progenitor cells. Analyses of the early steps of basal cell carcinoma formation show that this process requires reprogramming of interfolliclular epidermal cells to an embryonic hair follicle progenitor-like fate, with concomitant Wnt pathway activation.

Regulation of organ size is achieved through the action of the mTOR and Hippo signalling pathways, which control cell proliferation and cell growth in response to extracellular cues. A link between these pathways is revealed by the finding that YAP downregulates PTEN to promote cell growth and tissue hyperplasia.

Brown adipose tissue is intensively researched owing to its role in regulating energy and glucose homeostasis. Its differentiation is controlled through adrenergic-dependent regulation of the transcriptional co-regulator Prdm16. Adrenergic stimulation inhibits expression of miR-133a/b in a Mef2c-dependent manner to abrogate post-transcriptional silencing of Prdm16.

Epithelial to mesenchymal transition (EMT) is a fundamental process in both development and cancer progression. The transcription factor Elf5 is now reported as an upstream regulator of the key EMT inducer Snail2, and is shown to regulate the earliest known rewiring events required for tumour cell invasiveness and metastasis.

The pericentriolar material (PCM), the microtubule-organizing component of the centrosome, contains a multitude of proteins and is commonly described as an amorphous cloud surrounding the centrioles. However, the days of the PCM as an unstructured matrix are numbered. Using super-resolution microscopy, several reports have now revealed remarkable domain organization within the PCM.

Pluripotent stem cells (PSCs) express a distinctive set of microRNAs (miRNAs). Many of these miRNAs have similar targeting sequences and are predicted to regulate downstream targets cooperatively. These enriched miRNAs are involved in the regulation of the unique PSC cell cycle, and there is increasing evidence that they also influence other important characteristics of PSCs, including their morphology, epigenetic profile and resistance to apoptosis. Detailed studies of miRNAs and their targets in PSCs should help to parse the regulatory networks that underlie developmental processes and cellular reprogramming.

It is well documented that polyploid cells exist in mammalian tissues such as the placenta and liver, but their function and the mechanisms for their formation have remained elusive. Two studies now identify a role for atypical E2F transcription factors in promoting polyploidy in mammals and challenge present theories about the function of polyploidy.

Given the important role of the hypothalamus in regulating feeding and metabolism, there has been considerable interest in a possible function for hypothalamic stem cells in modulating body weight in health and disease. Mice given a high-fat diet develop inflammation in the hypothalamus and lose key types of neurons. It now appears that another effect of a high-fat diet is to reduce neural stem cell numbers, as well as their ability to make new neurons — effects that are associated with activation of the IKKβ/NF-κB pathway — thereby exacerbating the primary loss of neurons and resulting in altered feeding behaviour and obesity.

Focal adhesions are large structures through which integrins and scaffold proteins link the actin cytoskeleton to the extracellular matrix. A detailed analysis of integrin dynamics now indicates that focal-adhesion-associated integrins constantly switch between active and immobilized, and unbound and free-diffusing states, with different fibronectin-binding integrin heterodimers showing distinct focal-adhesion dynamics.

After food consumption, insulin-secreting pancreatic β-cells detect increased glucose and incretin hormones, and respond by releasing insulin. Wolfram syndrome 1, a protein that mitigates endoplasmic reticulum (ER) stress, is now shown to regulate insulin synthesis and release — revealing a molecular point of convergence between the ER stress and insulin release pathways.

Vascular endothelial growth factor (VEGF) signalling induces embryonic vascular development and angiogenesis in adult tissues. Direct phosphorylation of the actin-binding protein profilin by VEGF receptors is now shown to increase its affinity for actin, and to be essential for adult but not embryonic arteriogenesis.

The ESCRT (endosomal sorting complex required for transport) machinery is responsible for scission of the cytokinetic bridge that connects daughter cells at the end of mitosis. Specific endosomes are now found to mediate local bridge constriction and actin clearance in human cells, which contribute to the recruitment of ESCRT components at the abscission site.

It is widely assumed that peripheral membrane proteins induce intracellular membrane curvature by the asymmetric insertion of a protein segment into the lipid bilayer, or by imposing shape by adhesion of a curved protein domain to the membrane surface. Two papers now provide convincing evidence challenging these views. The first shows that specific assembly of a clathrin protein scaffold, coupled to the membrane, seems to be the most prevalent mechanism for bending a lipid bilayer in a cell. The second reports that membrane crowding, driven by protein–protein interactions, can also drive membrane bending, even in the absence of any protein insertion into the bilayer.

How cells sense and respond to physical forces is an area of intense investigation, which poses significant challenges for in vitro experiments and even greater obstacles for in vivo studies. Analyses of integrin complex dynamics in Drosophila melanogaster now provide evidence that altering mechanical force modulates the stability of integrin adhesion in vivo.

In a large-scale analysis, the effects of DNA damage on the levels and localization of almost every protein in an organism have now been tracked in living cells. It is shown that that although many proteins change their position or concentration, they rarely do both.

Kinesin-2 motors mediate anterograde intraflagellar transport (IFT) of IFT particles from the ciliary base to its tip, where particles are remodelled before retrograde transport by dynein 2 motors. Bardet-Biedl syndrome (BBS) and IFT-A proteins are now implicated in regulation of IFT assembly at the ciliary base and tip.